1. Field of the Invention
The invention relates to the field of chemical and pharmaceutical industry, specifically to a pharmaceutical composition for treatment of HIV infection, which contains at least one HIV protease inhibitor as an active ingredient, as well as pharmaceutically acceptable excipients with a specific quantitative component ratio. Additionally, the invention relates to a production process and to a treatment method.
2. Brief Description of the Related Art
According to the UN data, the number of HIV-positive people is 34.2 million. There is not a single country that has not been affected by this truly global epidemic.
In the Russian Federation the epidemiologic situation for HIV infection remains difficult, the spread of the human immunodeficiency virus among the population continues, and the cumulative amount of infected and sick individuals grows.
According to the Rospotrebnadzor data (The Federal Service for Supervision of
Consumer Rights Protection and Human Well-Being), there are 617,018 persons currently living with HIV in the Russian Federation.
During ten months of 2012, there were 62,865 new cases of HIV infection, which is 12.5% more compared to last year. HIV-cases are reported in all subjects of the Russian Federation.
HIV protease inhibitors (PI) are HIV protease active centre agonists, which should split the Gag-pol polyprotein of the virus into separate functional proteins. As the result of inhibitor action, protease cannot perform its function, and new viral particles, incapable of infecting new cells, are created. PI often has adverse effects on gastrointestinal (GI) tract. With long-term administration, lipidosis of various degrees, as well as lipodystrophy are possible.
Among HIV protease inhibitors are nelfinavir, saquinavir, tipranavir, darunavir, indinavir, atazanavir, ritonavir, lopinavir, palinavir, fosamprenavir.
It is well-known that most HIV protease inhibitors are substances of low water solubility. This may lead to technical complications during preparation of finished dosage forms based on these substances. Additionally, it is very difficult to select such excipient composition that would not lead to a worsening of pharmacokinetic properties of the finished dosage form and, thus, to a decrease of its bioavailability.
On the technical level, there is Kaletra® film-coated tablets (Lopinavir 200 mg+Ritonavir 50 mg) manufactured at Abbott GmBH and Co.KG, Germany, which is described in EA011924 patent and which was selected as a the prototype by the authors of the said invention.
As described in EA011924 patent, the authors tried to increase bioavailability of the solid dosage form of lopinavir+ritonavir. This problem was solved through addition of a relatively large amount of water-soluble polymers (from approximately 50 to approximately 85% w/w) and a pharmaceutically acceptable surfactant (from approximately 2 to approximately 20% w/w relative to the finished dosage form weight).
Use of relatively large amounts of high-cost excipients increases the net cost of the drug.
Additionally, a major disadvantage of lopinavir/ritonavir is its ability to cause not only gastro-intestinal problems (diarrhea, nausea), but also an express dyslipoproteinemia—even more significant, than with other PIs. Like other PIs, lopinavir/ritonavir leads to lipodystrophy syndrome; its incidence rate is 15% after 5 years, according to the data of a long-term study. Additionally, when prescribing this drug it is important to consider multiple drug interactions. In combination with efavirenz and nevirapine, and possibly amprenavir, its dosage should be increased. According to the latest data, lopinavir/ritonavir should be prescribed to be administered once a day (800/200 mg), although in this case, it causes diarrhoeamore often.
Thus, there is a current need in new antiviral finished dosage forms, which inhibit HIV protease activity and have improved pharmacokinetic and technological properties, as well as increased bioavailability and, consequently, improved therapeutic effectiveness.
Authors of the said invention set the following technical goal: development of new and more effective (compared to the prototype) pharmaceutical forms of the drug (HIV protease inhibitor) with the following properties: 1) the dosage form must have improved technological properties (durability, plasticity, disintegration time etc.), as well as high stability; 2) dosage form must have improved dissolution kinetics and increased bioavailability (compared to the prototype).
Attainable technical result of the claimed invention meets the set goals and expands the variety of high-quality domestic drugs available for treatment of HIV infection; it has improved dissolution kinetics and increased biological availability, as compared to the prototype. Additionally, produced dosage forms have improved technological properties and high shelf-life stability. Attained technical results are not obvious and could not have been foreseen by a specialist on the basis of modern technology level.